tbuckley/cabot-search huggingface dataset:
Abstract 5666: NAV-003, a full-length IgG1 bispecific antibody targeting a unique mesothelin epitope and CD3 to improve cytotoxicity against humoral immunosuppressed tumors
Authors: Luigi Grasso, Qun Jiang, Raffit Hassan, Nicholas C. Nicolaides, J. Bradford Kline
Journal: Cancer Research (2023)

Abstract Mesothelin (MSLN) is a cell surface protein over-expressed in a number of cancer types. Several antibody- and cellular-based MSLN targeting agents have been tested in clinical trials where their therapeutic efficacy has been moderate at best. Previous studies using antibody and CAR-T based agents have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found certain MSLN-positive tumors can produce proteins that can bind to subsets of IgG1-type antibodies and suppress their immune-effector activities. In an attempt to develop a more optimized anti-MSLN targeting agent, we engineered a humanized divalent anti-MSLN/anti-CD3ε bispecific antibody called NAV-003 that targets a MSLN epitope proximal to the tumor cell surface and an anti-CD3ε single-chain antibody capable of effectively binding, activating and directing T-cells to the surface of MSLN-bound tumor cells. NAV-003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV-003 demonstrated good tolerability and efficacy against patient-derived mesothelioma xenograft models co-engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV-003 clinical development and human proof-of-concept studies in patients with MSLN-expressing cancers. Citation Format: Luigi Grasso, Qun Jiang, Raffit Hassan, Nicholas C. Nicolaides, J. Bradford Kline. NAV-003, a full-length IgG1 bispecific antibody targeting a unique mesothelin epitope and CD3 to improve cytotoxicity against humoral immunosuppressed tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5666.
Abstract 3557: Stage-restricted osteoblasts specify signatures of osteosarcoma molecular subtypes
Authors: Jianning Tao, g Fan, Haydee Torres
Journal: Cancer Research (2023)

Abstract A challenging question in osteosarcoma research is the identity of the cell of origin, and its contribution to the molecular subtypes and signatures. We examine the potential of stage restricted osteoblasts to induce fully penetrant osteosarcoma using osteoblast stage specific Cre mice to mutate Trp53. We identified three molecularly distinct subtypes of osteosarcoma induced by the same driver mutation. Our results suggest that the three subtypes arise from different subpopulations of osteoblasts. Despite histologic identity as one entry osteosarcoma, these subtypes are separable based on molecular signatures and specific signaling pathways. These studies point to the cell of origin as a determinant of osteosarcoma molecular subtypes. Our studies may provide insights for understanding osteosarcoma heterogeneity and improving treatment of the disease. Citation Format: Jianning Tao, g Fan, Haydee Torres. Stage-restricted osteoblasts specify signatures of osteosarcoma molecular subtypes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3557.
Abstract 2396: Longitudinal monitoring of stromal stiffness predicts immune escape in preclinical hepatocellular carcinoma
Authors: Kiyoyuki Minamiguchi, Andrea Cortes, Patricia Da Costa Lopez, Malea Williams, Simone Anfossi, Marites Melancon, Rony Avritscher
Journal: Cancer Research (2023)

Abstract Background/Objectives: Increased tumor stiffness enhances disease progression and aggressiveness in several cancers. Stiffer extracellular tumor matrix hinders T cell trafficking and promotes immune escape. The interplay between liver tumor mechanical properties and hepatocellular immune cell landscape has not been fully investigated. The aim of our study is to correlate tumor stiffness quantified with shear wave elastography and tumor-infiltrating lymphocyte accumulation using a syngeneic orthotopic rat model of hepatocellular carcinoma (HCC). Methods: Rat hepatoma cell line McA-RH7777 were implanted in the left liver lobe of Buffalo rats. Maximum tumor size and stiffness were evaluated 3 weeks after implantation (baseline) and weekly for 14 days using ultrasound. The maximum tumor size of each rat was evaluated on transverse view of B-mode ultrasound. The elasticity of each rat was evaluated by shear wave elastography (SWE), and SWE measurements were obtained at the maximum tumor size in m/s. A circular region of interest was put manually on the SWE images to calculate tumor stiffness. SWE was performed 3 times for each rat at each time point, and the mean value of tumor stiffness was used for analysis. After 14 days, tumors were harvested for histology and immune cell isolation. Isolated cells were stained with CD3, CD4, CD8, CD25, CD45, CD103, CD161, CD279 (PD-1), FOXP3, IL17A, and INF-g and submitted to spectral cytometry. Results: Shear wave speed at baseline and at 14 days ranged from 1.95 to 3.07 m/s and from 2.25 to 3.26 m/s, respectively. The rate of longitudinal increase or decrease in tumor stiffness measured by SWE is inversely correlated with intratumoral infiltration of CD45+/CD3+, CD3+/CD8+ T cells and IFN-producing CD3+/CD8+ T cells (P=0.015, r=-0.62[-0.857, -0.15], P&amp;lt;0.01, r=-0.74[-0.913, -0.346], P=0.02, r=-0.6[-0.859, -0.107]). Intratumoral CD3+/CD4+ T cells did not significantly correlate with the rate of change in stiffness but did correlate with the rate of change in tumor size measured by B-mode ultrasound (P=0.03, r=-0.58[-0.850, -0.0730]). Conclusion: Our results confirm previous reports of immune escape in stiffer solid tumors in the context of HCC. Findings suggest that longitudinal monitoring of tumor stiffness can be useful for the assessment of immune cell infiltration. Citation Format: Kiyoyuki Minamiguchi, Andrea Cortes, Patricia Da Costa Lopez, Malea Williams, Simone Anfossi, Marites Melancon, Rony Avritscher. Longitudinal monitoring of stromal stiffness predicts immune escape in preclinical hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2396.
Abstract 4727: RAS and PP2A activities converge on phosphoregulation of epigenetic complexes in cancer
Authors: Mukund Sharma, Anna Aakula, Francesco Tabaro, Henrik Honkanen, Jesse Kamila, Matthieu Schapira, Cheryl Arrowsmith, Matti Nykter, Jukka K. Westermarck
Journal: Cancer Research (2023)

Abstract RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data, we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. In RAS-driven cancers, PP2A activity is inhibited by nuclear PP2A inhibitor proteins PME-1 and SET. We further demonstrate that these PP2A inhibitors drive oncogenic transcription, but that their transcriptional targets are highly diversified. Whereas PME-1 controls RAS and MYC-driven transcription, SET controls TP53 targets and G2/M checkpoint genes. We further provide evidence that these nuclear PP2A inhibitors significantly differ in their roles in regulating DNA methylation. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, the results provide a rich source for future understanding of phosphorylation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes. Citation Format: Mukund Sharma, Anna Aakula, Francesco Tabaro, Henrik Honkanen, Jesse Kamila, Matthieu Schapira, Cheryl Arrowsmith, Matti Nykter, Jukka K. Westermarck. RAS and PP2A activities converge on phosphoregulation of epigenetic complexes in cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4727.
Abstract 3898: Synergistic combination of the iron chelator deferasirox with cisplatin and doxorubicin chemotherapies against nonsmall cell lung carcinoma
Authors: Natalia I. Ortiz Alvelo, Grace Torres, Sthephanie Estrada, Daraishka Pérez, Yancy Ferrer, Yamixa Delgado
Journal: Cancer Research (2023)

Abstract Lung cancer is the second most common and leading cause of cancer-related deaths worldwide with 85% of these cases being non-small cell lung carcinoma (NSCLC). Unfortunately, despite improvements in NSCLC outcomes, many of these tumors develop resistance against principal chemotherapies (e.g., cisplatin (CisPt) and doxorubicin (Doxo)), inducing abysmally low survival prognosis. Deferasirox (Def), an FDA-approved iron chelation therapy, is a drug under study for cancer therapy due to iron plays a key role in cell growth and energy production. Herein, we determined the effect of Def alone and in combination with CisPt and Doxo on NSCLC A549 cells. Viability assays results showed that Def has synergistic cytotoxic effects in combination with CisPt and Doxo at low uM concentrations after 24 h of incubation using the Chou Talalay method. In addition, qPCR gene expression studies showed that Def induced a significant downregulation of EGFR, VEGF, MMP9, MMP2, CHD4 genes related to resistance and metastatic process. In addition, we determined the overexpression of NDRG1 gene mediated by Def confirming the chelation of iron and disruption of iron metabolism. Overall, this work will set the basis for adjuvant therapies against chemoresistance and metastasis processes using an iron chelator. Citation Format: Natalia I. Ortiz Alvelo, Grace Torres, Sthephanie Estrada, Daraishka Pérez, Yancy Ferrer, Yamixa Delgado. Synergistic combination of the iron chelator deferasirox with cisplatin and doxorubicin chemotherapies against nonsmall cell lung carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3898.
Abstract 3121: Exercise and tumor genomic landscapes in 2,879 patients with cancer
Authors: Brandon L. Tsai, Lydia Y. Liu, Stefan E. Eng, Whitney P. Underwood, Catherine P. Lee, Joshua W. Bliss, Paul C. Boutros, Lee W. Jones
Journal: Cancer Research (2023)

Abstract Approximately two-thirds of cancer diagnoses globally are attributed to modifiable lifestyle factors such as smoking, diet and inactivity. Conversely, regular exercise is linked to decreased risk of multiple cancers. However, the underlying molecular mechanisms are not fully elucidated. Specifically, how exercise impacts tumor genomic landscapes has not been considered. To address this gap, we integrated clinical annotation of exercise exposure with tumor mutational profiling of 2,879 patients with cancer. Exercise exposure was evaluated by validated questionnaire and tumor genomic profiling of ≥ 505 commonly mutated cancer genes was performed using the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actional Cancer Targets (MSK-IMPACT) assay. Among the most represented cancer types were breast (n = 623), lung (n = 524), endometrial (n = 260), colorectal (n = 217) and prostate (n = 176). We found that exercise influences the genomic landscapes of tumors in a cancer-type specific manner. For instance, breast, colorectal and lung cancers from exercising patients had significantly lower tumor mutation burden (TMB) compared with non-exercisers. TMB of melanoma was significantly higher in exercisers versus non-exercisers. A pan-cancer analysis showed that mutations in SMAD3 were more frequent among exercisers, while mutations in STK11, KEAP1 and RBM10 were more frequent among non-exercisers. Overall, this study shows that exercise regulates tumor genomic landscapes and does so in a cancer-site specific manner. Citation Format: Brandon L. Tsai, Lydia Y. Liu, Stefan E. Eng, Whitney P. Underwood, Catherine P. Lee, Joshua W. Bliss, Paul C. Boutros, Lee W. Jones. Exercise and tumor genomic landscapes in 2,879 patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3121.
Abstract 2123: Glycine decarboxylase regulates renal carcinoma progression via interferon stimulated gene factor 3-mediated pathway
Authors: Jin Young Kim, Mai Thi Tuyet Pham, Byung Hoon Kim, Ji Hae Seo, Sojin Shin, Eunyoung Ha
Journal: Cancer Research (2023)

Abstract Glycine decarboxylase (GLDC) is a mitochondrial enzyme that mediates the degradation of glycine as part of the glycine cleavage system; it is implicated as a tumor suppressor in hepatocellular carcinoma but as an oncogene in the lung cancer. Although GLDC expression in the kidney is second highest next to the liver, very little is known as to the role of GLDC in the kidney. Thus, this study was designed to determine the role of GLDC in the renal carcinoma. We found markedly increased expressions of GLDC in patients with renal cell carcinoma (RCC) classified as poor-risk group based on the Memorial Sloan Kettering Cancer Center prognostic model. In vitro studies revealed that cellular proliferation, colony formation, and migration were decreased in GLDC-deficient renal carcinoma cells while those were increased in GLDC-overexpressing renal carcinoma cells. In vivo xenograft studies with GLDC-deficient and -overexpressing cells also revealed that tumor sizes were noticeably decreased in GLDC-deficient cell-injected mice while those were increased in GLDC-overexpressing cell-injected mice. Mechanistically, we found GLDC regulates renal carcinoma progression via interferon (IFN) stimulated gene factor 3 (ISGF3)-mediated pathway. Poly-IC induced mRNA expression of IFN-α more strongly in GLDC-deficient cells. Expressions of IRF9 and STAT2 were increased in GLDC-deficient cells while those were decreased in GLDC-overexpressing cells. Interferon-responsive genes (IFIT1, IFI44, IFI44L, and IFI27) were also regulated by GLDC as evidenced by increased mRNA expressions in GLDC-deficient cells and increased mRNA expressions in GLDC-overexpressing cells. Knock-down of IRF9 and STAT2 in GLDC-deficient cells reversed decreased cellular proliferation, colony formation, and migration. In summary, the data in this study indicates that GLDC regulates renal carcinoma progression via ISFG3-medated pathway and lay a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of renal carcinoma. Citation Format: Jin Young Kim, Mai Thi Tuyet Pham, Byung Hoon Kim, Ji Hae Seo, Sojin Shin, Eunyoung Ha. Glycine decarboxylase regulates renal carcinoma progression via interferon stimulated gene factor 3-mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2123.
Abstract 252: A single-tube approach for detection of circulating tumor DNA using customized panels
Authors: Robert Meltzer, Jessalyn Kaur, Ekaterina Kintsurashvili, Christopher D'Amato, Tony Godfrey
Journal: Cancer Research (2023)

Abstract Circulating tumor DNA (ctDNA) is a promising biomarker for cancer. Applications of ctDNA analysis include screening, diagnosis, treatment selection, minimal residual disease (MRD) detection and recurrence monitoring. While some applications are best served by tumor-agnostic panels covering large regions of the genome, such large panels are not universally appropriate due to limitations in sensitivity, user-friendliness, turn-around time (TAT), and sequencing cost. One application where customized, tumor-informed panels can be preferable is detection of MRD and cancer recurrence, and multiple studies have shown that ctDNA can detect residual/recurrent disease several months earlier than routine clinical imaging. This application requires high sensitivity and in most cases will involve repeat testing of longitudinal samples collected over several months or years. In this scenario, the ideal assay characteristics include tumor-informed, personalized assay panels, with a simple, rapid workflow, and with minimal cost per assay. We have developed the Fluent LBx assay to meet these requirements. Fluent LBx analysis can be performed on-site in any appropriately equipped research or clinical laboratory, avoiding the extra cost and delay associated with external testing. Fluent LBx is a variation on SiMSen-Seq (PMID 27060140) that uses modified target and adapter primer sequences to facilitate barcoding and uniform amplification of multiple targets in a single-tube library construction protocol. Library preparation can be completed in under 1.5 hours with approximately 20 minutes of hands-on time. Using this approach, target DNA molecules are first barcoded and then amplified with indexed adaptors compatible with Illumina sequencers, in a single PCR reaction. After clean-up and sequencing, barcode information is used to compile reads from individual DNA molecules and minimize base calling errors introduced during PCR and sequencing. Here we present data demonstrating uniformity, sensitivity and specificity of Fluent LBx assays using LGC SeraCare quality control standards. Additionally, we present longitudinal clinical demonstration of residual disease detection from ctDNA collected from multiple head and neck and gastrointestinal cancer patients through longitudinal monitoring post therapeutic intervention. The Fluent LBx workflow allows rapid, inexpensive, patient-specific monitoring of MRD and recurrence in multiple cancer indications. Citation Format: Robert Meltzer, Jessalyn Kaur, Ekaterina Kintsurashvili, Christopher D'Amato, Tony Godfrey. A single-tube approach for detection of circulating tumor DNA using customized panels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 252.
Abstract 4440: Efficacy of Gen-1, an interleukin-12 immune gene therapy, at different dose frequencies
Authors: Subeena Sood, Jean D. Boyer, Jessica Kim, Majed M. Matar, Olivia Signer, Jennifer S. Rice, Alanna M. Smith, Nicholas Borys, Khursheed Anwer
Journal: Cancer Research (2023)

Abstract Introduction: The purpose of this study was to investigate the effect of dosing frequency on the antitumor activity of intraperitoneal GEN-1, an interleukin-12 (IL-12) immune gene therapy in a mouse model of peritoneally disseminated ovarian cancer. Procedures: Three GEN-1 dosing regimens were examined for efficacy in ID-8 tumor-bearing mice: weekly, every 2 weeks and every 3 weeks. 2.5 million cancer cells were bolus injected into 4 groups (B, C, and D) of 10 mice each. A control group (A) of 6 mice had PBS injected IP without tumor and an untreated control (E) of 15 mice were injected with 2.5 million cancer cells. Groups B, C, and D were injected with GEN-1 IP weekly, every 2 weeks, and every 3 weeks respectively. Six animals from each group B, C, and D were harvested for translational research (TR) after 5 weekly, 3 every 2-week and 2 every 3-week treatments respectively. The remaining 4 animals in each group were followed for weight change (tumor burden) and survival. Additionally, TR evaluated change in ascites T-cell, B-cell and myeloid cell populations. Results: There was a gradual rise in tumor burden and mortality in all treatment groups with comparable rate between once every week and once every 2-week regimens. Once every 3-week regimen had relatively higher mortality rate and higher tumor burden. There were similar or higher increases in T-cell and B-cells with reduced treatment frequency with lesser increases in myeloid cell density with reduced treatment frequency. Conclusions: Once every 2-week dosing of GEN-1 in human studies is warranted. Future combination studies of Gen-1 with immune checkpoint inhibitors will evaluate the safety and efficacy of this regimen. Citation Format: Subeena Sood, Jean D. Boyer, Jessica Kim, Majed M. Matar, Olivia Signer, Jennifer S. Rice, Alanna M. Smith, Nicholas Borys, Khursheed Anwer. Efficacy of Gen-1, an interleukin-12 immune gene therapy, at different dose frequencies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4440.